The present invention relates to adamantane derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
Adamantane derivatives are known in the art, e.g. from WO 95/04720 for use as gastrin and cholecystokinin receptor ligands, from Chem. Abs. (1977), Volume 86, No. 13 (86: 89560d) for use as analgesics, and from U.S. Pat. No. 3,464,998 as antibiotics.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1xcex2(IL 1xcex2l ) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes and mesangial cells.
It would be desirable to make compounds effective as P2X7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X7 receptor may play a role.
In accordance with the present invention, there is therefore provided a compound of general formula 
wherein
m represents 1, 2 or 3, preferably 1 or 2;
each R1 independently represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom, preferably a hydrogen atom;
A represents C(O)NH or, preferably, NHC(O);
Ar represents a group 
X represents a bond, an oxygen atom or a group CO, (CH2)1-6, CHxe2x95x90, (CH2)1-6O, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CRxe2x80x2(OH), (CH2)1-3O(CH2)1-3, (CH2)1-3O(CH2)2-3O, NR5, (CH2)1-6NR5, NR5(CH2)1-6, (CH2)1-3NR5(CH2)1-3, O(CH2)2-6NR5, O(CH2)2-3NR5(CH2)1-3, (CH2)1-3NR5(CH2)2-3O, NR5(CH2)2-6O, NR5(CH2)2-3O(CH2)1-3, CONR5, NR5CO, S(O)n, S(O)nCH2, CH2S(O)n, SO2NR5 or NR5SO2;
n is 0, 1 or 2;
Rxe2x80x2 represents a hydrogen atom or a C1-C6 alkyl, preferably methyl, group;
one of R2 and R3 represents a halogen, cyano, nitro, amino, hydroxyl, or a group selected from (i) C1-C6 alkyl optionally substituted by at least one C3-C6 cycloalkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C6 alkyloxy optionally substituted by at least one C3-C6 cycloalkyl, and (iv) C3-C8 cycloalkyloxy, each of these groups being optionally substituted by one or more fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen atom;
either R4 represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7, or R4 represents a 3- to 8-membered saturated carbocyclic ring system substituted by one or more substituents independently selected from xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6N7, the ring system being optionally further substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl;
r is 1, 2, 3, 4, 5 or 6;
R5 represents a hydrogen atom or a C1-C6 alkyl or C3-C8 cycloalkyl group;
R6 and R7 each independently represent a hydrogen atom or a C1-C6 alkyl, C2-C6 hydroxyalkyl or C3-C8 cycloalkyl group, or R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring; with the provisos that,
(a) when A represents C(O)NH and R4 represents an unsubstituted 3- to 8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and
(b) when A represents C(O)NH and X represents a group (CH2)1-6 or O(CH2)1-6, then R4 does not represent an unsubstituted imidazolyl, unsubstituted morpholinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl group, and
(c) when A represents NHC(O) and R4 represents an unsubstituted 3- to 8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and
(d) when A represents NHC(O) and X represents O(CH2)1-6, NH(CH2)1-6 or SCH2, then R4 does not represent an unsubstituted 1-piperidinyl or unsubstituted 1-pyrrolidinyl group, and
(e) when A represents NHC(O) and X represents O(CH2)2-3NH(CH2)2, then R4 does not represent an imidazolyl group;
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched. Examples of alkyl groups/moieties containing up to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. When one of R2 and R3 represents a C1-C6 alkyl/C1-C6 alkyloxy optionally substituted by at least one C3-C6 cycloalkyl, it should be understood that one or both of the alkyl and cycloalkyl moieties may be optionally substituted by fluorine atoms. In relation to R4, a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom may be a monocyclic or bicyclic ring system. Further in relation to R4, a 3- to 8-membered saturated carbocyclic ring system may be a monocyclic or bicyclic ring system. When R6 or R7 represents a C2-C6 hydroxyalkyl in the substituent NR6R7, xe2x80x94(CH2)rNR6R7 or xe2x80x94CONR6R7, it will be appreciated that the hydroxyl group will not be bonded to the same carbon atom as the nitrogen atom. When R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring, the ring obtained is monocyclic.
Preferably X represents a bond, an oxygen atom or a group CO, (CH2)1-6, CHxe2x95x90, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CRxe2x80x2(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n or S(O)nCH2.
One of R2 and R3 represents a halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, nitro, amino, hydroxyl, or a group selected from (i) C1-C6 alkyl, preferably C1-C4 alkyl, optionally substituted by at least one (e.g. 1, 2 or 3) C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (ii) C3-C8 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (iii) C1-C6 alkyloxy, preferably C1-C4 alkyloxy, optionally substituted by at least one (e.g. 1, 2 or 3) C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and (iv) C3-C8 cycloalkyloxy (e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), each of these groups being optionally substituted by one or more (e.g. 1, 2, 3 or 4) fluorine atoms, and the other of R2 and R3 represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom.
Preferably, one of R2 and R3 represents a halogen (especially chlorine or bromine) atom or a nitro, amino or C1-C6 alkyl (especially methyl or ethyl) group and the other of R2 and R3 represents a hydrogen atom.
R4 may represent a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6 alkyl, preferably C1-C4 alkyl, C1-C6 hydroxyalkyl, preferably C1-C4 hydroxyalkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7.
The 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system in the group R4 may be a monocyclic ring system such as pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl or 3-pyrrolidinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl), 4-piperiden-3-yl, piperazinyl (e.g. 1-piperazinyl), homopiperazinyl, 
or a bicyclic ring system such as 
Alternatively, R4 may represent a 3- to 8-membered saturated carbocyclic ring system substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7, the ring system being optionally further substituted by one or more (e.g. 1, 2, 3 or 4) substituents independently selected from fluorine atoms, hydroxyl and C1-C6 alkyl, preferably C1-C4 alkyl.
The 3- to 8-membered saturated carbocyclic ring in the group R4 is preferably a monocyclic ring system such as a cyclopentyl or cyclohexyl ring.
Specific examples of groups R4 include: 
When X represents a bond or a group CO, (CH2)1-6, O(CH2)2-6, O(CH2)2-3O(CH2)2-3, (CH2)1-3O(CH2)2-3, NR5(CH2)2-6, (CH2)1-3NR5(CH2)2-3, O(CH2)2-3NR5(CH2)2-3, NR5(CH2)2-3O(CH2)2-3, NR5CO, SO2 or NR5SO2, R4 preferably represents a group: 
When X represents an oxygen or sulphur atom or a group CHxe2x95x90, (CH2)1-6O, OCH2, O(CH2)2-6O, O(CH2)2-3OCH2, CRxe2x80x2OH, (CH2)1-3OCH2, (CH2)1-3O(CH2)2-3O, NR5, (CH2)1-6NR5, O(CH2)2-6NR5, NR5CH2, (CH2)1-3NR5CH2, O(CH2)2-3NR5CH2, (CH2)1-3NR5(CH2)2-3O, NR5(CH2)2-6O, NR5(CH2)2-3OCH2, CONR5, SO, S(O)nCH2, CH2S(O)n or SO2NR5, R4 preferably represents a group: 
R5 represents a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or C3-C8, preferably C3-C6, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) group.
R6 and R7 each independently represent a hydrogen atom, or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), C2-C6 hydroxyalkyl or C3-C8, preferably C3-C6, cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) group, or R6 and R7 together with the nitrogen atom to which they are attached form a 3- to 8-membered, preferably 3- to 6-membered, saturated heterocyclic ring such as a pyrrolidinyl or piperidinyl ring.
Preferred compounds of the invention include:
2-Nitro-3-piperazin-1-yl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Amino-3-piperazin-1-yl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
2-Chloro-3-piperazin-1-yl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-piperazin-1-yl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
5-(4-Amino-1-piperidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-5-(3-Amino-1-pyrrolidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-piperazin-1-ylmethyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]-N-(tricyclo[3.3.1.1 3,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
5-[(4-Amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
5-[(3-Amino-1-pyrrolidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(R)-2-Chloro-5-(2-pyrrolidinylmethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(S)-2-Chloro-5-(2-pyrrolidinylmethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(3-piperidinylmethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
cis-5-[(4-Aminocyclohexyl)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Methyl-5-(1-piperazinylmethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(1-piperazinylmethyl)-N-(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-2-Chloro-5-(3-pyrrolidinyloxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-2-Chloro-5-(3-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
trans-5-[(4-Aminocyclohexyl)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
cis-(+/xe2x88x92)-5-[(3-Aminocyclopentyl)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
(S,S)-2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-N-(tricyclo[3.3.1.13,7dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(2-methyl 1-piperazinyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-2-Chloro-5-(3-pyrrolidinyloxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-5-(3-Amino-1-piperidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
(+/xe2x88x92)-2-Chloro-5-(3-piperidinylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
N-[2-methyl-5-(4-piperidinyloxy)phenyl]-tricyclo[3.3.1.13,7]decane-1-acetamide, hydrochloride salt,
N-[2-chloro-5-(4-piperidinyloxy)phenyl]-tricyclo[3.3.1.13,7]decane-1-acetamide, hydrochloride salt,
2-Chloro-5-[(4-piperidinylamino)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[[[4-(Aminomethyl)cyclohexyl]amino]methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[[(4-Aminocyclohexyl)amino]methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[(1-Azabicyclo[2.2.2]oct-3-ylamino)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
N-[4-(3-Aminopyrrolidin-1-yl)-2-methylphenyl]-2-(tricyclo[3.3.1.13,7]dec-1-yl)acetamide, dihydrochloride salt,
N-(2-Methyl-4-piperazin-1-ylphenyl)-2-(tricyclo[3.3.1.13,7]dec-1-yl)acetamide, dihydrochloride salt,
cis-4-(3-Amino-cyclopentyloxy)-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro4-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-2-Chloro-4-(pyrrolidin-3-yloxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-4-(piperidin-3-yloxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro4-(4-piperazin-1-yl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-4-(3-pyrrolidinylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-4-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
(xc2x1)-5-[(3-Amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
trans-2-Chloro-5-[[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
cis-2-Chloro-5-[(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-piperidinylidenemethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-hydroxy-piperidin-4-yl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Ethyl-5-piperazin-1-ylmethyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperidin-4-ylsulfanyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperidin4-ylsulfinyl)-N-(tricyclo[3.3.1.13.7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-(piperidin4-ylsulfonyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperidin4-ylmethylsulfanyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperidin4-ylmethanesulfonyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(piperazine-1-carbonyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-([1,4]diazepane-1-carbonyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
4-Chloro-N1-(piperidin4-yl-)-N2-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-isophthalamide, hydrochloride salt,
2-Chloro-5-(hydroxy4-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7dec-1-ylmethyl)-benzamide, hydrochloride salt,
(xc2x1)-2-Chloro-5-(hydroxy-3-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Bromo-5-piperazin-1-ylmethyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(1-piperazinyl)ethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
5-[2-(4-Amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(3-piperidinylamino)ethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[2-(3-Amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(3-pyrrolidinylamino)ethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, dihydrochloride salt,
5-[2-[(3R)-3-Aminopyrrolidinyl]ethyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-[2-(hydroxymethyl)-1-piperazinyl]ethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)-benzamide, hydrochloride salt,
(+/xe2x88x92)-5-(3-Amino-1-pyrrolidinyl)-2-chloro-N-(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(4-piperidinylcarbonyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[1-hydroxy-1-(4-piperidinyl)ethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(1-piperazinyl)ethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(4-piperidinyl)ethoxy)-N-(tricyclo[3.3.1.13,7dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-(4-piperidinyloxy)ethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[2-[2-(1-piperazinyl)ethoxy]ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[(5,6-dihydro-1(4H)-pyrimidinyl)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide,
2-Chloro-5-[[4-[(2-hydroxyethyl)amnino]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-[[4-hydroxy4-[[(1-methylethyl)amino]methyl]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7dec-1-ylmethyl)-benzamide,
2-Chloro-5-[(1,2,3,6-tetrahydro-3-pyridinyl)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, hydrochloride salt,
2-Chloro-5-(3-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, acetate salt,
2-bromo-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]dec -1-ylmethyl-benzamide, and
2-Chloro-5-[(E)-3-piperidinylidenemethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide.
The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises:
(i) when X represents a CH2 group, R4 represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7 and R4is linked to X through a nitrogen atom, reacting a compound of general formula 
wherein one of R10 and R11 represents a hydrogen atom and the other of R10 and R11 represents a group xe2x80x94CH2L1 in which L1 represents a leaving group (e.g. a halogen atom) and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x2xe2x80x94Hxe2x80x83xe2x80x83(III)
xe2x80x83in the presence of a base (e.g. diisopropylethylamine), wherein R4xe2x80x2 represents a 3- to 9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atoms and optionally an oxygen atom, the heterocyclic ring system being optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6 alkyl, C1-C6 hydroxyalkyl, xe2x80x94NR6R7, xe2x80x94(CH2)rNR6R7 and xe2x80x94CONR6R7 and wherein R6 and R7 are as defined in formula (I); or
(ii) when X represents an oxygen atom or a group O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, O(CH2)2-6NR5 or O(CH2)2-3NR5(CH2)1-3, reacting a compound of general formula 
wherein one of R12 and R13 represents a hydrogen atom and the other of R12 and R13 represents a hydroxyl group and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Yxe2x80x94OHxe2x80x83xe2x80x83(V)
wherein Y represents a bond or a group (CH2)1-6, O(CH2)2-6, (CH2)1-3O(CH2)2-3, NR5(CH2)2-6 or (CH2)1-3NR5(CH2)2-3 and R4 is as defined in formula (I), in the presence of 1,1-(azodicarbonyl)dipiperidine and tributylphosphine (under conditions of the Mitsunobu reaction: Tetrahedron Lett. (1993), 34, 1639); or
(iii) when X represents a bond, an oxygen atom or a group O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3 and A is NHC(O), reacting a compound of general formula 
wherein one of R14 and R15 represents a group xe2x80x94Xxe2x80x2xe2x80x94R4 and the other of R14 and R15 represents a hydrogen atom, Xxe2x80x2 represents a bond, an oxygen atom or a group O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3, L2 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3, R4 and R5 are as defined in formula (I), with a compound of general formula 
wherein m and R1 are as defined in formula (I), optionally in the presence of a coupling agent (e.g. 1,1xe2x80x2-carbonyldiimidazole); or
(iv) when X represents a bond, an oxygen atom or a group O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3 and A is C(O)NH, reacting a compound of general formula 
wherein R2 and R3 are as defined in formula (I) and R14 and R15 are as defined in formula (VI) in (iii) above, with a compound of general formula 
wherein m and R1 are as defined in formula (I), in the presence of a base (e.g. diisopropylamine); or
(v) when X represents a bond or a group NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3, reacting a compound of general formula 
wherein one of R16 and R17 represents a leaving group, L3, such as a halogen atom and the other of R16 and R17 represents a hydrogen atom and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of general formula
R4xe2x80x94Zxe2x80x83xe2x80x83(XI)
wherein Z represents a hydrogen atom or a group NHR5, (CH2)1-6NHR5, O(CH2)2-6NHR5 or a group (CH2)1-3O(CH2)2-3NHR5 and R4 and R5 are as defined in formula (I), optionally in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BINAP) and a base (e.g. cesium carbonate); or
(vi) when X represents a group CH2O, reacting a compound of formula (II) as defined in (i) above with a compound of formula (V) as defined in (ii) above wherein Y represents a bond, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (e.g. silver trifluoromethanesulfonate); or
(vii) when X represents a group CH2NR5, reacting a compound of formula (II) as defined in (i) above with a compound of formula (XI) as defined in (v) above wherein Z represents a group NHR5; or
(viii) when X represents a group CH2O(CH2)1-3 or CH2O(CH2)2-3O, reacting a compound of formula (II) as defined in (i) above with a compound of formula (V) as defined in (ii) above wherein Y represents a group (CH2)1-3 or O(CH2)2-3, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (e.g. silver trifluoromethanesulfonate); or
(ix) when X represents a group CH2NR5CH2 or CH2NR5(CH2)2-3O reacting a compound of formula (II) as defined in (i) above with a compound of formula (XI) as defined in (v) above wherein Z represents a group CH2NHR5 or O(CH2)2-3NHR5; or
(x) when X represents a group CH2 and R4 represents an unsubstituted 4- to 6-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, reacting a compound of formula (II) as defined in (i) above, with a compound of general formula 
wherein s and t independently represent 1 or 2; or
(xi) when X represents a group CO, CONR5, NR5CO, SO2, NR5SO2 or SO2NR5 and A is NHC(O), reacting a compound of general formula 
wherein one of R18 and R19 represents a group xe2x80x94Xxe2x80x3xe2x80x94R4 and the other of R18 and R19 represents a hydrogen atom, Xxe2x80x3 represents a group CO, CONR5, NR5CO, SO2, NR5SO2 or SO2NR5, L4 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3, R4 and R5 are as defined in formula (I), with a compound of formula (VI) as defined in (iii) above, optionally in the presence of a coupling agent (e.g. 1,1xe2x80x2-carbonyldiimidazole); or
(xii) when X represents a group CO, CONR5, NR5CO, SO2, NR5SO2 or SO2NR5 and A is C(O)NH, reacting a compound of general formula 
wherein R2 and R3 are as defined in formula (I) and R18 and R19 are as defined in formula (XII) in (xi) above, with a compound of formula (IX) as defined in (iv) above, in the presence of a base (e.g. diisopropylamine); or
(xiii) when X represents a sulfur atom, reacting a compound of formula (X) as defined in (v) above, with an organolithium reagent such as n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x80x94Sxe2x80x94SO2xe2x80x94Tolxe2x80x83xe2x80x83(XV)
wherein Tol represents a tolyl group (4-methylphenyl) and R4 is as defined in formula (I); or
(xiv) when X represents a CHOH or CH2 group, reacting a compound of formula (X) as defined in (v) above, with an organolithium reagent (e.g. methyllithium/t-butyllithium or n-butyllithium at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x80x94CHOxe2x80x83xe2x80x83(XVI)
wherein R4 is as defined in formula (I), optionally followed by a reduction reaction, e.g. with methyloxalylchloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile; or
(xv) when X represents a bond, reacting a compound of formula (X) as defined in (v) above, with an organolithium reagent such as n-butyllithium (e.g. at xe2x88x9270xc2x0 C.) and then with a compound of general formula
R4xe2x95x90Oxe2x80x83xe2x80x83(XVII)
wherein R4 is as defined in formula (I), optionally followed by a reduction reaction, e.g. with methyloxalylchloride and triethylamine followed by tributyltin hydride in the presence of azobisisobutyronitrile;
(xvi) when X represents a group SO, oxidising a corresponding compound of formula (I) in which X represents a sulphur atom (e.g. using, as oxidising agent, 3-chloroperoxybenzoic acid or potassium peroxymonosulphate (commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d)); or
to (xvii) when X represents a group SCH2, reacting a compound of formula (X) as defined in (v) above, with an organolithium reagent (e.g. methyllithium and/or t-butyllithium at xe2x88x9270xc2x0 C.) and then with a compound of general formula 
wherein R4 is as defined in formula (I); or
(xviii) when X represents a group SOCH2 or SO2CH2, oxidising a corresponding compound of formula (I) in which X represents a group SCH2 (e.g. using, as oxidising agent, 3-chloroperoxybenzoic acid or potassium peroxymonosulphate (commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d)); or
(xix) when X represents a group CHxe2x95x90, reacting a compound of formula (II) as defined in (i) above with trimethyl phophite and then with a compound of formula (XVII) as defined in (xv) above in the presence of a base (e.g. lithium diisopropylamide); or
(xx) when X represents a group (CH2)1-6, reacting a compound of general formula 
wherein one of R20 and R21 represents a group CHO or a group (CH2)1-5CHO and the other of R20 and R21 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of general formula (XX), R4xe2x80x94H, wherein R4 is as defined in formula (I), in the presence of a reducing agent (e.g. sodium triacetoxyborohydride, in a suitable solvent such as dichloroethane); or
(xxi) when X represents a group (CH2)1-6NR5, (CH2)1-3NR5(CH2)1-3 or (CH2)1-3NR5(CH2)2-3O, reacting a compound of formula (XIX) as defined in (xx) above, with a compound of general formula (XXI), R4xe2x80x94Zxe2x80x2, wherein Zxe2x80x2 represents a group NHR5, (CH2)1-3NHR5, O(CH2)2-3NHR5 and R4 and R5 are as defined in formula (I), in the presence of a reducing agent (e.g. sodium triacetoxyborohydride, in a suitable solvent such as dichloroethane); or
(xxii) when X represents a group (CH2)1-3O(CH2)1-3 or (CH2)1-3O(CH2)2-3O, reacting a compound of formula (XIX) as defined in (xx) above in which one of R20 and R21 represents a group CHO or a group (CH2)1-2CHO and the other of R20 and R21 represents a hydrogen atom, with a reducing agent (such as sodium borohydride), followed by reaction with a compound of general formula (XXII), R4xe2x80x94E, wherein E represents a group (CH2)1-3L5 or O(CH2)2-3L5, L5 is a leaving group (such as a halogen atom or a sulphonate ester group, e.g. p-toluenesulphonate) and R4 is as defined in formula (I), in the presence of a base (such as sodium hydride); or
(xxiii) when X represents a group (CH2)1-6, reacting a compound of formula (II) as defined in (i) above with trimethylphosphite and then with a compound of formula (XVI) as defined in (xiv) above, a compound of formula (XVII) as defined in (xv) above or a compound of general formula (XVIA), R4(CH2)1-4CHO in which R4 is as defined in formula (I), in the presence of a base (e.g. lithium diisopropylamide), followed by a reduction reaction (for example, with hydrogen and a platinum oxide catalyst); or
(xxiv) when X represents a group (CH2)2-6O, reacting a compound of general formula 
wherein one of R22 and R23 represents a group (CH2)2-6L6 and the other of R20 and R21 represents a hydrogen atom, L6 represents a leaving group (e.g. a halogen atom or a sulphonate ester group such as p-toluenesulphonate) and m, A, R1, R2 and R3 are as defined in formula (I), with a compound of formula (V) as defined in (ii) above in which Y represents a bond; or
(xxv) when X represents a group CRxe2x80x2(OH) in which Rxe2x80x2 is a C1-C6 alkyl group, oxidising a corresponding compound of formula (I) in which X represents CH(OH) (e.g. using the oxidant dimethylsulphoxide/oxalyl chloride), followed by reaction with a C1-C6 alkyllithium reagent; or
(xxvi) when X represents a group CH2S, reacting a compound of formula (II) as defined in (i) above with a compound of general formula (XXIV), R4xe2x80x94SH, wherein R4 is as defined in formula (I), in the presence of a base (e.g. sodium hydride); or
(xxvii) when X represents a group CH2SO or CH2SO2, oxidising a corresponding compound of formula (I) in which X represents a group CH2S (e.g. using, as oxidising agent, 3-chloroperoxybenzoic acid or potassium peroxymonosulphate (commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d)); or
(xxviii) when X represents a group CH2 and R4 represents a 3-piperidinyl or 2-piperazinyl group, reacting a compound of formula (II) as defined in (i) above with a reagent formed by combining pyridine or pyrazine with an aluminium hydride reagent (e.g. lithium aluminium hydride), followed by a reduction reaction (e.g. with hydrogen and a platinum catalyst); or
(xxix) when X represents a group CHxe2x95x90 and R4 represents a 3-piperidinyl group, reacting a compound of general formula 
wherein one of R24 and R25 represents an aldehyde group xe2x80x94CHO, and the other of R24 and R25 represents a hydrogen atom and m, A, R1, R2 and R3 are as defined in formula (I), with 2,3,4,5-tetrahydropyridine (Bull. Chem.Soc.Jpn. 1983, 56, 3199), followed by a reduction reaction (e.g. with sodium borohydride in a protic solvent such as methanol); or
(xxx) when X represents a bond, NR5 or NR5(CH2)1-6 and R4 represents a carbon-linked piperidyl or piperazinyl group, reducing a compound of general formula 
wherein one of R26 and R27 represents a pyridyl, pyrazinyl, NR5-pyridyl, NR5-pyrazinyl, NR5(CH2)1-6-pyridyl or NR5(CH2)1-6-pyrazinyl group and the other of R26 and R27 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in formula (I), with a source of hydrogen and a hydrogenation catalyst (such as platinum oxide); or
(xxxi) when X represents a group CH2O(CH2)1-3 or CH2O(CH2)2-3O and A is NHC(O), reacting a compound of general formula 
wherein one of R28 and R29 represents a group xe2x80x94Xxe2x80x2xe2x80x3xe2x80x94R4 and the other of R28 and R29 represents a hydrogen atom, Xxe2x80x2xe2x80x3 represents a group CH2O(CH2)1-3 or CH2O(CH2)2-3O, is L7 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3 and R4 are as defined in formula (I), with a compound of formula (VII) as defined in (iii) above, optionally in the presence of a coupling agent (e.g. 1,1xe2x80x2-carbonyldiimidazole); or
(xxxii) when X represents a group CH2O(CH2)1-3 or CH2O(CH2)2-3O and A is C(O)NH, reacting a compound of general formula 
wherein R2 and R3 are as defined in formula (I) and R28 and R29 are as defined in formula (XXVII) in (xxxi) above, with a compound of formula (IX) as defined in (iv) above, in the presence of a base (e.g. diisopropylamine);
and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), (xxiii), (xxiv), (xxv), (xxvi), (xxvii), (xxviii), (xxix), (xxx), (xxxi) or (xxxii) converting the compound of formula (I) to a further compound of formula (I) and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dioxane, xylene or dimethylformamide, at a temperature, e.g. in the range from 0 to 200xc2x0 C., preferably in the range from 0 to 150xc2x0 C.
Compounds of formula (II) in which A is NHC(O) may be prepared by reacting a compound of general formula 
wherein L10 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2 R3, R10 and R11 are as defined in formula (II), with a compound of formula (VII) as defined above, optionally in the presence of a coupling agent (e.g. 1,1xe2x80x2-carbonyldiimidazole).
Compounds of formula (XXX) in which one of R10 and R11 represents a hydrogen atom and the other of R10 and R11 represents a group xe2x80x94CH2L1 and L1 represents a bromine atom can be prepared by reacting a compound of general formula 
wherein one of R30 and R31 represents a hydrogen atom and the other of R30 and R31 represents a methyl group and R2 and R3 are as defined in formula (I), with N-bromosuccinimide and catalytic azobisisobutyronitrile or dibenzoylperoxide, optionally followed by chlorination with oxalyl chloride and catalytic dimethylformamide or with thionyl chloride.
Compounds of formula (II) in which A is C(O)NH and L1 represents, for example, a bromine atom may be prepared by reacting a compound of general formula 
wherein R2 and R3 are as defined in formula (I) and R30 and R31 are as defined in formula (XXXI) above, with a compound of formula (IX) as defined above, in the presence of a base (e.g. diisopropylethylamine), followed by reaction with N-bromosuccinimide and catalytic azobisisobutyronitrile or dibenzoylperoxide.
Compounds of formula (IV) in which A is NHC(O) may be prepared in an analogous manner to compounds of formula (II) in which A is NHC(O), using instead of the intermediate compound of formula (XXX), an intermediate compound of general formula 
wherein L11 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3, R12 and R13 are as defined in formula (IV).
Compounds of formula (IV) in which A is C(O)NH may be prepared by reacting a compound of general formula 
wherein R2, R3, R12 and R13 are as defined in formula (IV), with a compound of formula (IX) as defined above, optionally in the presence of a base (e.g. diisopropylethylamine).
Compounds of formula (VI) can be prepared by reacting a compound of general formula 
wherein R32 represents a hydrogen atom or a C1-C6 alkyl group, one of R33 and R34 represents a leaving group, L12, such as a halogen atom (e.g. bromine or iodine) or a trifluoromethanesulfonate group and the other of R33 and R34 represents a hydrogen atom, and R2 and R3 are as defined in formula (VI), with a compound of general formula
xe2x80x83Hxe2x80x94Xxe2x80x2xe2x80x94R4xe2x80x83xe2x80x83(XXXVI)
wherein Xxe2x80x2 and R4 are as defined in formula (VI), in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BINAP) and a base (e.g. cesium carbonate) (1996 J. Am. Chem. Soc., 7215-6; 1997 J. Am. Chem. Soc., 3395), followed by a hydrolysis reaction (e.g. with sodium hydroxide) and optionally a chlorination reaction (e.g. with oxalyl chloride and catalytic dimethylformamide or with thionyl chloride).
Compounds of formula (VII) may conveniently be prepared by reacting a compound of formula (VI) in which L2 represents a hydroxyl group with diphenylphosphoryl azide in the presence of a base such as triethylamine.
Compounds of formula (X) in which A is NHC(O) may be prepared in an analogous manner to compounds of formula (II) in which A is NHC(O), using instead of the intermediate compound of formula (XXX), an intermediate compound of general formula 
wherein L13 represents a leaving group (e.g. a hydroxyl or chloride leaving group) and R2, R3, R16 and R17 are as defined in formula (X).
Compounds of formula (X) in which A is C(O)NH may be prepared in an analogous manner to compounds of formula (IV) in which A is C(O)NH, using instead of the intermediate compound of formula (XXXIV), an intermediate compound of general formula 
wherein R2, R3, R16 and R17 are as defined in formula (X).
Compounds of formula (XII) can be prepared as described in Syn. Lett. (1998)379-380.
Compounds of formula (XIII) in which Xxe2x80x3 represents a group CO, CONR5, SO2 or SO2NR5 can be prepared by reacting a compound of general formula 
wherein one of R35 and R36 represents a group COL14 or SO2L14 and the other of R25 and R26 represents a hydrogen atom, L14 represents a leaving group (e.g. a halogen atom), R37 represents a hydrogen atom or a C1-C6 alkyl group, and R2 and R3 are as defined in formula (XIII), with a compound of formula (XXXVI) in which Xxe2x80x2 represents a bond or a group NR5, in the presence of a base such as diisopropylethylamine and catalytic dimethylaminopyridine, followed by a hydrolysis reaction (e.g. sodium hydroxide) and, optionally, a chlorination reaction (e.g. with oxalyl chloride and catalytic dimethylformamide or with thionyl chloride).
Compounds of formula (XIII) in which Xxe2x80x3 represents a group represents a group NR5CO or NR5SO2 can be prepared by reacting a compound of general formula 
wherein one of R38 and R39 represents a group NHR5 and the other of R38 and R39 represents a hydrogen atom, R37 is as defined for compound (XXXIX), and R2 and R3 are as defined in formula (XIII), with a compound general formula (XLI), R4xe2x80x94J, wherein J represents a group COCl or SO2Cl and R4 is as defined in formula (I), in the presence of a base such as diisopropylethylamine.
Compounds of formula (XIV) may conveniently be prepared by reacting a compound of formula (XIII) in which L4 represents a hydroxyl group with diphenylphosphoryl azide in the presence of a base such as triethylamine.
Compounds of formula (XIX) in which one of R20 and R21 represents a group (CH2)1-5CHO and the other of R20 and R21 represents a hydrogen atom can be prepared by oxidising a compound of general formula 
wherein one of R40 and R41 represents a group (CH2)2-6OH and the other of R40 and R41 represents a hydrogen atom, and m, A, R1, R2 and R3 are as defined in formula (I), using as the oxidising agent, for example, Dess Martin Periodinane reagent.
Compounds of formula (XLII) in which one of R40 and R41 represents a group (CH2)2OH and the other of R40 and R41 represents a hydrogen atom can be prepared from a compound of general formula (X) as defined above, an organolithium reagent such as methyllithium (at xe2x88x9270xc2x0 C.) followed by n-butyllithium (at xe2x88x9270xc2x0 C.), and then treatment with ethylene oxide.
Compounds of formula (XLII) in which one of R40 and R41 represents a group (CH2)3-6OH and the other of R40 and R41 represents a hydrogen atom can be prepared by reacting a compound of general formula (X) as defined above with a compound of general formula 
in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), followed by reduction with, for example, hydrogen and a platinum oxide catalyst.
Compounds of formula (XIX) in which one of R20 and R21 represents a group CHO and the other of R20 and R21 represents a hydrogen atom (which are equivalent to compounds of formula (XXV)) can be prepared from a compound of general formula (X) as defined above, with an organolithium reagent such as methyllithium (at xe2x88x9270xc2x0 C.) followed by n-butyllithium (at xe2x88x9270xc2x0 C.) and then with dimethylformamide.
Compounds of formula (XXIII) in which L6 represents an iodine atom or p-toluenesulphonyloxy group may be prepared by reacting a compound of formula (XLII) as defined above with iodine/triphenylphosphine/imidazole or with a sulphonyl chloride such as p-toluenesulphonyl chloride, in the presence of a base such as diisopropylethylamine.
Compounds of formula (XXVI) in which one of R26 and R27 represents a pyridyl or pyrazinyl group and the other of R26 and R27 represents a hydrogen atom can be prepared from a compound of formula (X) as defined above by reaction with a pyridyl or pyrazinyl boronic acid in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0).
Compounds of formula (XXVI) in which one of R26 and R27 represents a NR5-pyridyl, NR5-pyrazinyl, NR5(CH2)1-6-pyridyl or NR5(CH2)1-6-pyrazinyl group and the other of R26 and R27 represents a hydrogen atom can be prepared from a compound of formula (X) as defined above by reaction with a compound NHR5pyridyl, NHR5pyrazinyl, NHR5(CH2)1-6-pyridyl or NHR5(CH2)1-6-pyrazinyl, in the presence of a palladium catalyst (e.g. palladium acetate), a phosphine ligand (e.g. BINAP) and a base (e.g. cesium carbonate).
Compounds of formulae (III), (V), (VII), (IX), (XI), (XV), (XVI), (XVIA), (XVII), (XVII), (XX), (XXI), (XXII), (XXIV), (XXVII), (XXVIII), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII) and (XLIII) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, compounds of formula (I) in which one of R2 and R3 represents a nitro group can be converted to compounds of formula (I) in which one of R2 and R3 represents an amino group by reduction using iron powder and ammonium chloride in ethanol/water under reflux conditions. The latter compounds can in turn be converted into compounds of formula (I) in which one of R2 and R3 represents a halogen atom, e.g. chlorine, by diazotization (e.g. with sodium nitrite) and reaction with copper chloride. Compounds of formula (I) in which R6 or R7 represents a hydrogen atom can be converted to compounds of formula (I) in which R6 or R7 represents a C1-C6 alkyl, C2-C6 hydroxyalkyl, C3-C8 cycloalkyl or a 3- to 8-membered saturated heterocyclic ring by standard chemical procedures.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of the present invention are advantageous in that they possess pharmacological activity. They are therefore indicated as pharmaceuticals for use in the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn""s disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer""s disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term xe2x80x9ctherapyxe2x80x9d also includes xe2x80x9cprophylaxisxe2x80x9d unless there are specific indications to the contrary. The terms xe2x80x9ctherapeuticxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d should be construed accordingly.
The invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
The invention also provides a method of treating an obstructive airways disease (e.g. asthma or COPD) which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (I)/salt/solvate (active ingredient) may be in the range from 0.001 mg/kg to 30 mg/kg.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w, more preferably from 30 to 99.90% w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.